DESCRIPTION: Primary open-angle glaucoma and normal pressure glaucoma are sight threatening, age-related, eye disease that are often associated with intraocular pressure (IOP). Current treatments of the diseases are based on lowering the IOP, by pharmacological or surgical means, to prevent further degeneration of the optic nerve and loss of vision. Recent investigations on the cellular basis of neuronal degeneration in general, and the optic nerve in particular, have led to speculation that therapies directly aimed at preventing, slowing or reversing glaucomatous optic neuropathy can be developed. The long-term objective of this work is the identification of a class of compounds that could be developed as a pharmacological neuroprotective agents for the treatment of patients with glaucomatous optic neuropathy. Significant observations, made by this laboratory in human glaucomatous tissue, have described the presence of NOS-1, -1, -3, as well as COX-1 and -2, in the optic nerve head. Some of these pathways may contribute to neurodestruction in this tissue. The completion of the proposed specific aims: 1) identification of which isoforms of nitric oxide synthase (NOS) and cyclooxygenase (COX) pathways are upregulated or induced in human glaucomatous optic neuropathy, 2) demonstration of these specific pathways in the rat eye during optic nerve degeneration, and 3) study of the pharmacological inhibition of these specific pathways in a rat model of elevated IOP, will advance the development of the next generation of drugs to treat glaucoma. The proposed investigations are designed to first extend the observations in humans, by using immunohistochemistry, in situ hybridization, and reverse transcriptase-polymerase chain reaction, so that specific isoform pathways can be targeted for study in the rat. In the rat, optic nerve degeneration will be modeled using three approaches: chronic, moderately elevated IOP by three scleral vessel cautery, retinal ischemia by acute elevated IOP, and optic nerve transection. Specific pharmacological intervention will be tested in the rat model against NOS and COS isoform pathways that are identified in human glaucomatous tissue and potentially contributing to neurodestruction.